Submissions for variant NM_000059.4(BRCA2):c.818C>T (p.Ser273Leu)

gnomAD frequency: 0.00001  dbSNP: rs80359068

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000686235	SCV000813744	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 273 of the BRCA2 protein (p.Ser273Leu). This variant is present in population databases (rs80359068, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 33646313). ClinVar contains an entry for this variant (Variation ID: 566428). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002424586	SCV002681187	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-05	criteria provided, single submitter	clinical testing	The p.S273L variant (also known as c.818C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide position 818. The serine at codon 273 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. This alteration was previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8). In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002424586	SCV003848053	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478403	SCV004220593	uncertain significance	not provided	2023-05-04	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0000041 (1/244264 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. A functional study showed inconclusive results regarding the variant's impact on protein function (PMID: 36707518 (2023)). In the published literature, the variant has been reported in an individual with early onset breast cancer (PMID: 25503501 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV004004244	SCV004846828	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 273 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown this variant impacts suppression and repair of ssDNA gaps, but does not impact homology-directed DNA repair or increase sensitivity to PARP inhibitors (PMID: 36707518). This variant has been reported in at least one individual affected with breast cancer (PMID: 25503501). This variant has been identified in 1/244264 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.